The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present invention.
Hematopoiesis is a complex process in which hematopoietic stem cells are capable of self-renewal to maintain a long-term supply of progenies and are stimulated to differentiate into multiple lineages by various growth factors. It is assumed that the majority of hematopoietic stem cells are in the quiescent (G0) phase of the cell cycle, and only a few actively cycling hematopoietic stem cells supply all the hematopoietic cells at a given time. This concept is supported by evidence that quiescent hematopoietic stem cells are resistant to the cytotoxic effects of 5-fluorouracil (5-FU), whereas most of the cycling counterparts are sensitive to 5-FU, thus resulting in myelosuppression.
Myelosuppression is the most common adverse effect of cytotoxic chemotherapy and is a major limiting factor in the clinical treatment of cancer. Therefore, promotion of hematopoiesis remains an extremely important challenge in cancer therapy. A large number of cytokines have been screened for their chemoprotective potential. Administration of recombinant colony-stimulating factors, such as granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), and stem cell factor (SCF), alleviates chemotherapy-induced myelotoxicity augmenting proliferation of hematopoietic progenitor cells in the bone marrow and accelerates the recovery of peripheral blood cells.
There are three members of the interleukin-1 (IL-1) gene family: IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1Ra). IL-1α and IL-1β are receptor agonists and IL-1Ra is a specific receptor antagonist. IL-1α and IL-1β are synthesized as 31 kDa precursors. Processing of IL-1α and IL-1β to “mature” forms of 17 kDa requires specific cellular proteases. IL-1Ra is the first described naturally occurring specific receptor antagonist of any cytokine or hormone-like molecule. IL-1Ra is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structure variants of IL-1Ra have previously been described: a 17 kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and a 18 kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). Secretory IL-1Ra (sIL-1Ra) is synthesized as a 177 amino acid protein, with cleavage of a 25 amino acid leader sequence prior to secretion as a variably glycosylated 152 amino acid protein.